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Chronic Versus Acute Transplantation of Neural Tissues for TBI-Induced Cortical Injuries

Award Number: R01NS119472
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Chronic Versus Acute Transplantation of Neural Tissues for TBI-Induced Cortical Injuries - PROJECT SUMMARY/ABSTRACT Injury to the cerebral cortex occurs frequently across the spectrum of severity in traumatic brain injury (TBI). No therapies exist to counter the neurological and cognitive deficits caused by these injuries, which are responsible for substantial disability after TBI. A promising strategy for restoring brain function after injury is cell replacement. Neural tissues that connect with host cortex locally and function as supplementary cortical processing modules are especially intriguing candidates for this approach. Currently available tissue substrates that are suitable for translation, including human brain organoids derived from patient-matched stem cell lines, do not fully recapitulate the architecture or micro-circuitry of cortex. However, they can still be used to investigate outstanding questions regarding neural tissue integration with the host brain. One essential issue that has not been examined systemically is the optimal timing of cell replacement after TBI. The overall objective of the current proposal is to evaluate how the interplay between the timing of neural tissue transplantation after TBI and the state of the cortical microenvironment affects anatomic and functional outcomes. Our central hypothesis is that acute neural tissue transplantation after TBI and removal of the injury perimeter will improve outcomes as a result of enhanced integration of graft neurons with host brain networks and maintenance of host cortex integrity. To test this hypothesis, we will transplant human cortical organoids into rat visual cortex in the chronic or acute setting after a controlled cortical impact injury and assess anatomic and functional outcome measures. In Aim 1, organoids will be transplanted directly into a chronic injury cavity or after resection of the glial scar at the border of the cavity. In Aim 2, organoid grafts will be inserted directly into an acute injury cavity or after the injury margin as been removed. In both of these Aims, organoid health and cell composition as well as host cortex integrity will be assessed histologically. The extent of formation of graft efferents (green fluorescent protein tracing) and afferents (modified rabies virus system for retrograde trans-synaptic tracing) also will be determined. Functional integration of organoid grafts with the host cortex will be investigated using in vivo techniques for recording extracellular neural activity and visual stimulation of the host animal. In Aim 3, we will examine how modulating the activity of organoids using optogenetic stimulation impacts their connectivity and integration with the chronically or acutely injured brain. The proposed research is innovative in its use of human brain organoids as structured neural tissues for cortical repair after TBI and because it explicitly assesses how the timing of transplantation affects outcomes. We expect that the proposed studies will elucidate conditions that result in improved outcomes after organoid transplantation while also identifying the limitations of currently available neural tissue substrates. These expected outcomes will advance the field of cortical repair after TBI by reinvigorating the concept of cell replacement therapy and inspiring novel strategies for modulating graft integration with the brain to achieve specific therapeutic goals.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $393,446 )
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	7/2/2024	NON-COMPETING CONTINUATION	$393,446
														Subtotal = $393,446

Issue Date FY: 2023 ( Subtotal = $405,614 )
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	6/30/2023	NON-COMPETING CONTINUATION	$405,614
														Subtotal = $405,614

Issue Date FY: 2022 ( Subtotal = $411,139 )
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	7/1/2022	NON-COMPETING CONTINUATION	$411,139
														Subtotal = $411,139

Issue Date FY: 2021 ( Subtotal = $415,714 )
2021	2021	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/14/2021	NEW	$415,714
														Subtotal = $415,714

Grand Total All Awards = $1,625,913

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Chronic Versus Acute Transplantation of Neural Tissues for TBI-Induced Cortical Injuries

Award Number: R01NS119472

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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